tbuckley/cabot-search huggingface dataset:
Biomarker evolution after neoadjuvant systemic therapy in breast cancer.
Authors: Dan Ran Castillo, Seyed Saeed Pairawan, Laura Denham, Sharon S. Lum, Gayathri Nagaraj
Journal: Journal of Clinical Oncology (2022)

e12615 Background: Tumor heterogeneity is one of the hallmarks of breast cancer (BC) and has major implications for treatment response and resistance. Currently, there are no specific guidelines regarding biomarker reassessment on residual tumor post-neoadjuvant systemic therapy (NAST). In this study, we compared biomarker discordance between pre- and post-NAST tumors at our institution and determined if actionable changes were observed. We also report the impact of the detected biomarkers differences on the choice of adjuvant treatment. Methods: We conducted a retrospective review of BC patients who received NAST followed by definitive surgery from 2004 to 2020. The initial tissue biopsies were tested for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status per ASCO/CAP guidelines and repeated on the residual tumor tissue after NAST. Descriptive statistics was used to compare clinicopathologic characteristics. The biomarkers were compared using Wilcoxon’s t test and McNemar’s test. Concordance analysis of intrinsic subtypes was evaluated by Cohen’s kappa method. Results: Out of 434 patients who undergone surgical resection following NAST, 95 (22%) patients were identified to have repeat biomarker testing of residual invasive BC post NAST. 30 out of the 96 patients were found to discordant receptor status on repeat biomarker testing. In this cohort of thirty patients with discordant biomarkers, median age was 51.5 (29-70 years), 33.3% cases had stage II, and 56.7% had stage III BC. 66.75 patients were ER positive and/or PR positive, 20% patients were HER2 positive with one triple positive, and 13.3% patients were triple negative on pre-NAST tumors. Majority of the retesting was performed on breast tissue (90%, n = 27). The biomarker change was noted in 11 out of 30 (36.7%) for ER, 12 out of 30 (40%) for PR, and 13 out of 30 (43.3%) for HER2 marker. Concordance analysis demonstrated that HER2 was the most prone to change (Cohen K = -0.003) from pre-NAST to post-NAST specimen, whereas ER (Cohen k = 0.26) and PR (Cohen k = 0.18) were less subject to change. Kappa assumes theoretical maximum value of 1 when pre- and post-NAST are in agreement, a negative value indicates a poor concordance. One third of patients with discordant biomarkers had additional adjuvant treatment. 8 out of 30 patients (26.7%) were started on adjuvant anti-HER2 therapy due to HER2 positivity on post-NAST tumors. After ER positivity was detected on residual BC tumors, 2 initial triple negative patients (6.7%) were initiated on adjuvant endocrine therapy. Conclusions: Biomarker discordance due to tumor heterogeneity is an increasingly recognized phenomenon. Given the prognostic and therapeutic implications of biomarker driven BC management, retesting biomarkers routinely after NAST on residual invasive tumor would be beneficial in this patient population.
Neoadjuvant atezolizumab plus docetaxel/oxaliplatin/capecitabine in non-metastatic gastric and gastroesophageal junction adenocarcinoma: The PANDA trial.
Authors: Yara L. Verschoor, Liudmila Kodach, José van den Berg, Johanna W. van Sandick, Jolanda van Dieren, Sara Balduzzi, Cecile Grootscholten, Xander Veenhof, Koen Hartemink, Marieke A. Vollebergh, E.C. Owers, Annemarieke Bartels-Rutten, Peggy den Hartog, Monique E van Leerdam, Ton Schumacher, Emile E. Voest, John B. A. G. Haanen, Myriam Chalabi
Journal: Journal of Clinical Oncology (2022)

4059 Background: Immune checkpoint blockade improves clinical outcomes for patients with gastric and gastro-esophageal junction (GEJ) cancers, but its efficacy and impact on the tumor microenvironment in non-metastatic, resectable disease remains largely unknown. Peri-operative FLOT, the current standard-of-care, leads to pathologic complete responses (pCR) and major pathologic responses (MPR) in 16% and 37% of patients, respectively. An important open question is whether PDL-1 blockade monotherapy can prime the tumor microenvironment in a favorable manner, prior to combination with chemotherapy. Methods: We report results from the phase 2 PANDA trial (NCT03448835) of neoadjuvant atezolizumab (anti-PDL-1) plus docetaxel, oxaliplatin, and capecitabine (DOC) in patients with resectable gastric or GEJ adenocarcinoma. Patients received a single cycle of atezolizumab monotherapy, followed by 4 cycles of atezolizumab+DOC. Tumor tissue was collected at baseline, after atezolizumab monotherapy, the first atezolizumab+DOC, and at resection. The primary endpoints were safety and feasibility in 20 patients, and secondary endpoints included MPR (&lt;10% viable tumor rest) and disease-free survival. Results: Twenty patients, of which 18 with mismatch repair (MMR) proficient and two with MMR-deficient tumors, were evaluable for safety and efficacy analyses. MPR was observed in 14/20 patients (70%; 95% CI 46–88%), including 9 pCR (45%; 95% CI 23-68%). Among patients with intestinal type adenocarcinoma, 12/15 (80%; 95% CI 52-96%) had an MPR, with 9/15 (60%; 95% CI 32-84%) pCR. Treatment was well tolerated, with two patients (10%) experiencing a grade 3 immune adverse event. At a median follow-up of 29 months (IQR 16-34), 15 patients (75%) were alive and disease-free. None of the patients with an MPR recurred. All patients underwent resections without treatment-related delays and no unexpected surgical complications were documented. Translational analyses, including baseline PDL-1 CPS score and whole exome sequencing (WES), plus CD8 T-cell infiltration and RNA sequencing at 4 timepoints will be presented at the meeting. Conclusions: Our data show that the addition of atezolizumab to neoadjuvant chemotherapy leads to promising pathologic responses in gastric/GEJ adenocarcinoma, which appears to be higher than in historical controls, with no recurrences in responders. These data should be validated in a large randomized controlled trial. Clinical trial information: NCT03448835.
Re-activation of HIF signalling pathway in the epicardium improves heart regeneration after myocardial infarction
Authors: E Gamen, EL Price, D Pezzolla, C De Villiers, M Gunadasa-Rohling, R Salama, DR Mole, T Bishop, CW Pugh, RP Choudhury, CA Carr, JM Vieira, PR Riley
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background In mouse, cardiac regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential, however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explore a role for hypoxia inducible factor (HIF) family of transcription factors on the regulation of epicardial activity which is essential for cardiac response to injury. Purpose HIF signalling might be involved in the quiescence of the epicardium observed in the first week of life. Thus, HIF stabilisation may induce epicardial re-activation and extend the 7-day regenerative window in a neonate mouse model of myocardial infarction (MI). Methods We analysed epicardial expression of HIF signalling during embryonic development, and in a regenerative post-natal day 1 (P1) versus non-regenerative (P7) mouse model by single cell RNA-sequencing. Next, we established in vitro epicardial explants to confirm the role of HIF signalling in epicardial activation, and finally we induced MI by permanent ligation of the proximal left anterior descending (LAD) coronary artery in P7 mice to test weather HIF signalling re-activation improved heart regeneration in a non-regenerative model. Results Expression of both HIF-1α and HIF-2α is very pronounced at early stages of heart development and gradually decreases throughout gestation. The epicardium preferentially expresses HIF-1α by embryonic day (E) 16.5. Postnatally, GO term analysis showed an enrichment of hypoxia-related pathways in P1 compared to P7 hearts, largely in the epicardial cell population. Accordingly, expression of Phd2, encoding for the main suppressor of HIF signalling, was enriched in P7 derived epicardial cells. Notably, the increase in Phd2 levels coincided with a clear reduction in the expression of Wilms’ tumour 1 (Wt1) in P7 versus P1 hearts, a key player in the epicardial activation. In vitro studies on epicardial explants confirmed regulation of WT1 expression and migration capacity following genetical and pharmacological modulation of HIF signalling. Finally, in vivo targeting of PHD enzymes through pharmacological inhibition with clinically approved drugs in a neonatal mouse model of MI led to prolonged epicardial activation, increased vascularisation, augmented infarct resolution and preserved cardiac function up to 3 weeks after injury. Conclusions Together, these findings show that modulation of HIF signalling can regulate epicardial activity and improve heart regeneration capacity beyond the 7-day regenerative window and may represent a viable therapeutic strategy for treating ischaemic heart disease.
Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient?
Authors: David Kegyes, Catalin Constantinescu, Louise Vrancken, Leo Rasche, Celine Gregoire, Bogdan Tigu, Diana Gulei, Delia Dima, Alina Tanase, Hermann Einsele, Stefan Ciurea, Ciprian Tomuleasa, Jo Caers
Journal: Journal of Hematology & Oncology (2022)

Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant.
Adherence to adjuvant endocrine therapy assessed by data from prescription renewals and medical records from tamoxifen in Swedish patients with cytochrome P450 2D6 (CYP2D6) genotyped early breast cancer.
Authors: Linda Thoren, Sara Margolin, Erik Eliasson, Jonas C. S. Bergh, Jonatan D. Lindh
Journal: Journal of Clinical Oncology (2022)

542 Background: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been suggested. The main aim of this study was to investigate the consistency between prescription refill data and reports from medical records on adherence to AET in early breast cancer. We also studied if there was an association between menopausal status, CYP2D6 activity, estimated risk for recurrence and adherence to AET. Methods: 1235 pre-and postmenopausal Swedish breast cancer patients operated 2006 – 2014, genotyped for CYP2D6, who initiated adjuvant tamoxifen treatment, were included in the study. Information on AET was retrospectively collected from both medical records and the Swedish Prescribed Drug Registry. Consistency was defined as dispensed doses of AET divided by AET intake documented in medical records. Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate (MPR) ≥ 80 %. Subgroup analyses were performed based on menopausal status, recurrence-risk and CYP2D6 activity. Results: In 84% of the patients the consistency of AET between the sources of information was within 80-125%. Consistency &lt; 80% was most frequent in premenopausal/high risk patients and CYP2D6 Poor Metabolizers (PM). Among 899 patients with at least 4.5 years follow up, adherence to tamoxifen was 72% according to prescription refill data, compared to 77% as reported by medical records. When including aromatase inhibitors adherence increased to 82% and 88%. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PM had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). Conclusions: Consistency between medical records and dispensing data on adherence was better than anticipated. Adherence to AET was good, 82% when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a reduced risk of side effects according to previous studies. Further work is needed to clarify the impact of CYP2D6 activity on adherence to tamoxifen.
SURG-15. A Case Series of Pediatric Patients with Brain Tumors and Perioperative COVID-19 Infection
Authors: John Emmanuel Torio, Ronnie Baticulon, Anna Patricia Alcasabas
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Surgery in patients diagnosed with COVID-19 is associated with increased risk of morbidity and mortality, especially within 6 weeks of SARS-CoV-2 infection. Furthermore, most studies have focused on adults, and little is known about perioperative outcomes in children with COVID-19. METHODS: We reviewed the operative census of the Division of Neurosurgery of Philippine General Hospital from March 2020 until December 2021. We identified all pediatric patients with brain tumors and confirmed COVID-19 infection within two weeks of their neuro-oncologic surgery. Their clinical course and outcomes are described herein. RESULTS: Four patients were included in this case series: three had tumors in the cerebellum, one in the pineal region. All of them were boys, with ages ranging from 4 months to 13 years. All tumors were malignant, and two were confirmed to be medulloblastoma after tumor resection. COVID-19 infection was diagnosed by the presence of SARS-CoV-2 RNA through a nasopharyngeal swab. Three patients acquired the virus post-operatively, likely from nosocomial transmission. In the remaining patient, it was community-acquired. All the patients had chest radiographs consistent with pneumonia but none had marked elevation of serum inflammatory markers. No patient received remdesivir or tocilizumab. At the time of their presentation, either the COVID-19 vaccine was not yet available in the country, or the patient was not yet eligible for vaccination. One patient died because of brain herniation from tumor progression, two were discharged and eventually underwent adjuvant therapy, and one remained in-hospital as of this writing. DISCUSSION: COVID-19 infection resulted in delays in the management of patients with pediatric CNS tumors. Given the high risk of these patients for potential complications, consensus guidelines must be established to achieve good outcomes and prolong survival.
Incidence of severe and febrile neutropenia in cancer patients treated with myelosuppressive chemotherapy in real clinical oncology practice: Preliminary results from the FLAME study.
Authors: Anton Snegovoy, Inessa Kononenko, Alexandra Chernova, Artem Shepel, Liliya Kaleikina, Anna Shalina, Sergey Sharov, Elena Pavlova, Petr Goldshmidt, Alexander Dergunov, Rustem Safin, Irina Pimonova, Denis Yukalchuk, Svetlana Soroka, Viktorya Mikhaluk, Liubov Yu Vladimirova, Marina Yavorskaya, Tatiyana Starostina, Svetlana Tkachenko, Irina Sorokina
Journal: Journal of Clinical Oncology (2022)

e18740 Background: Febrile neutropenia (FN) is a life-threatening complication of myelosuppressive chemotherapy (CT). It can lead to infections, subsequent hospitalizations, treatment delays, dose reductions, and additional health care costs. According to guidelines, use of granulocyte colony-stimulating factors (G-CSF) prevents FN. However, in clinical practice, the need for G-CSF use has not been defined due to the lack of national reports on neutropenic complications (NC). Methods: FLAME is the first Russian retrospective non-randomized non-interventional study designed to include 515 patients (pts) with solid tumors receiving myelosuppressive CT with or without targeting and immuno-oncology drugs. The primary objective of this study is to define the actual incidence of NC in clinical practice and to identify patients at high risk of FN. In addition, this study is intended to demonstrate the unmet need for G-CSF prophylaxis of FN. Patients who completed at least the first 2 cycles of treatment in frame of the course between the 1 st ’Aug 2020 till 30 th ’October 2021 were eligible to be included in the study. Results: Data were obtained from 492 pts recruited from cancer hospitals throughout Russia. Their characteristics were as follows: median age 56.5; male/female: 36.5%/63.5%. Among 492 pts with various malignancies, 65% had stage III or IV. Breast (68%), colorectal (10%), urogynecological cancer (10%) were the most common. The remaining were gastrointestinal cancer, lung cancer, sarcoma, and CUP. Clinically significant comorbidities were reported in 53.6% of pts. Thirty percent of patients had ≥1 risk factor for FN based on individual and CT analysis. From 29 different CT regimens, 14% had a high risk of FN. Primary prophylaxis was given only to 44.1% pts with a high risk of FN [empegfilgrastim (Extimia®) 19,1%, filgrastim 25%]. The duration of filgrastim administration was 1 to 3 days in 81% of cases. Treatment of NC with corticosteroids and others was prescribed in 12.8% of cases. Three percent (3%) and 3.8% of pts had FN and dose-limiting neutropenia, respectively. Delayed CT at the second cycle was performed in 27%. The dose of CT was reduced by 20-25% in 8.3% of patients. Conclusions: Preliminary results from this study suggest that the risk of FN is higher from the start of CT. Delaying and reducing the dose of CT is still typical for oncologists. This practice is associated with low adherence to guidelines. Further efforts are needed to decrease the risk of NC in clinical practice.
Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis
Authors: Karolina Gaebe, Alyssa Y Li, Amy Park, Ambica Parmar, Benjamin H Lok, Arjun Sahgal, Kelvin K W Chan, Anders W Erickson, Sunit Das
Journal: The Lancet Oncology (2022)
A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.
Authors: Gerald Steven Falchook, Manish R. Patel, Susanna Varkey Ulahannan, Daniela Maier, Susanne Hipp, Hisaya Azuma, David R. Spigel
Journal: Journal of Clinical Oncology (2022)

TPS3175 Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.
Impact of urinary incontinence on sexual function in patients presenting for lower urinary tract symptoms
Authors: G. Fallara, L. Boeri, L. Candela, A. Costa, P. Capogrosso, F. Belladelli, E. Pozzi, M. Raffo, C. Corsini, D. Cignoli, N. Schifano, W. Cazzaniga, G. Colandrea, A. D'Arma, R. Matloob, V. Mirone, F. Montorsi, A. Salonia
Journal: European Urology (2022)
IMMU-20. Effective CAR-T cell medulloblastoma therapy in an immunocompetent mouse model
Authors: Rania Tsahouridis, Chaemin Lim, Marina Sokolsky, Gianpietro Dotti, Timothy Gershon
Journal: Neuro-Oncology (2022)

Abstract Immunotherapy with chimeric antibody receptor (CAR) T cells is effective for previously incurable hematologic cancers and may transform treatment for refractory brain tumors. However, CAR-T cell therapy for solid tumors has not yet been as successful as for leukemias, and animal models are needed to improve implementation. At present, preclinical studies of CAR-T cell therapy for brain tumors have typically used exogenous tumors, xenografted into immunocompromised mice, because primary mouse brain tumors do not express antigens that match brain tumor-specific antigens in humans. To advance preclinical development of CAR-T brain tumor therapy, we engineered mice to develop medulloblastomas that express B7-H3, an antigen specifically expressed on human medulloblastomas and other pediatric brain tumors. We show that treating these tumors with B7-H3-directed CAR-T cells provokes anti-tumor responses both in vitro and in vivo. Administering B7-H3 CAR-T cells by intracranial injection increased the event-free survival time of mice with medulloblastoma, in a dose-dependent manner. CAR-T cell treatment was not curative as an isolated intervention, suggesting that cure will require pairing with surgical resection and additional adjuvant therapy. Our model presents new opportunities to study the mechanisms of CAR-T cell efficacy and recurrence in an immunocompetent host with intact vasculature and blood-brain barrier. Our ongoing studies using scRNA-seq will allow us to define therapy-induced changes in tumor cells, CAR-T cells and cells of the tumor microenvironment and to test new T-cell modifications and combinations of therapeutic modalities, toward a goal of optimizing CAR-T cell therapy for pediatric brain tumors.